The Allosteric Regulator Inositol Phosphate Dramatically Affects the Efficacy and Selectivity of Inhibitors for...

Area of Science:

• Biochemistry and Molecular Biology
• Epigenetics and Gene Regulation
• Pharmacology and Drug Discovery

Background:

• Class I histone deacetylases (HDACs) are key regulators of gene transcription and significant therapeutic targets.
• HDAC1-3 function as catalytic subunits within diverse multiprotein complexes, yet inhibitors are seldom studied in this context.
• The influence of allosteric regulators like inositol phosphates on HDAC inhibitor activity remains underexplored.

Purpose of the Study:

• To investigate the complex-dependence of multiple HDAC inhibitors.
• To evaluate the impact of inositol phosphates on HDAC inhibitor potency.
• To assess the in vitro versus in vivo relevance of HDAC inhibitor efficacy.

Main Methods:

• Assayed multiple HDAC inhibitors against seven distinct HDAC complexes.
• Investigated the effect of inositol phosphates on inhibitor potency, particularly benzamides with foot-pocket groups.
• Utilized cell-based assays to measure histone acetylation and HDAC degradation.

Main Results:

• HDAC inhibitor profiles exhibited significant dependence on the specific HDAC complex, despite targeting the same enzyme.
• Inositol phosphates caused substantial, complex-selective reductions in the potency of specific benzamide inhibitors.
• Observed potential discrepancies between in vitro and in vivo potencies due to inositol phosphate presence.

Conclusions:

• HDAC inhibitor efficacy is profoundly influenced by the specific HDAC complex and the presence of allosteric regulators like inositol phosphates.
• Benzamide inhibitors with foot-pocket groups, proposed for HDAC1/2 selectivity, show significantly altered potency in the presence of inositol phosphates.
• Future evaluation of HDAC inhibitors (HDACi) must consider their behavior within native complexes and physiological conditions for accurate in vivo prediction.